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WO2000050428A1 - Procede de preparation de derives de l'acide (-)pyridobenzoxazine carboxylique - Google Patents

Procede de preparation de derives de l'acide (-)pyridobenzoxazine carboxylique Download PDF

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Publication number
WO2000050428A1
WO2000050428A1 PCT/KR2000/000145 KR0000145W WO0050428A1 WO 2000050428 A1 WO2000050428 A1 WO 2000050428A1 KR 0000145 W KR0000145 W KR 0000145W WO 0050428 A1 WO0050428 A1 WO 0050428A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
formula
iii
carbon atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2000/000145
Other languages
English (en)
Inventor
Young-Jun Park
Ho-Seong Lee
Min-Hwan Kim
Kyung-Chul Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Samsung Electronics Co Ltd
Original Assignee
Samsung Electronics Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Samsung Electronics Co Ltd filed Critical Samsung Electronics Co Ltd
Priority to US09/674,323 priority Critical patent/US6316618B1/en
Priority to DE60009807T priority patent/DE60009807T2/de
Priority to EP00905443A priority patent/EP1073662B1/fr
Priority to BRPI0005132-2A priority patent/BR0005132B1/pt
Publication of WO2000050428A1 publication Critical patent/WO2000050428A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a process for preparing an optically active (-) 9-fluoro-3-methyl-7- oxo-2, 3-dihydro-7H-pyrido [1,2, 3-de] [1,4] -benzoxazine-6- carboxylic acid derivative ("pyridobenzoxazine carboxylic acid derivative”) represented by the formula (I) or pharmaceutically acceptable salt thereof having an excellent antimicrobial activity.
  • Ri represents hydrogen atom or lower alkyl group having 1 to 5 carbon atoms.
  • optically active pyridobenzoxazine carboxylic acid derivatives have been prepared and used as active ingredients for antibiotic agents, since the compounds are known to possess higher antimicrobial activity and weaker toxicity than optically inactive racemic mixture (see: Drugs of the Future, 17(2), 559- 563 (1992) ) .
  • optically active (-) pyridobenzoxazine carboxylic acid derivatives have been prepared in the art by the following two processes: the first one comprises a step of selective hydrolysis of ( ⁇ )7,8- fluoro-2, 3-dihydro-3-acetoxymethyl-4H- [1,4] -benzoxazine by hydrolase; and, the second one comprises a step of optical resolution of ( ⁇ ) 7, 8-fluoro-2, 3-dihydro-3- acetoxymethyl-4H- [1, 4] -benzoxazine by chemical reagent (see: EP 206,283; Korean Pat. No. 60,571).
  • the present inventors successfuly prepared optically active (-) pyridobenzoxazine carboxylic acid derivative, by employing a starting material of (+) ethyl 2- (4-chloro-5-fluoro-2-halo-3-nitobenzoyl) -3- [ (1- hydroxypropy-2 (S) -yl) amino] acrylate which is obtainable from low-priced 4-chloro-5-fluorobenzoic acid derivative instead of high-priced 4 , 5-difluorobenzoic acid derivative, and substituting piperazine for chlorine atom.
  • a primary object of the present invention is, therefore, to provide a process for preparing optically active (-) pyridobenzoxazine carboxylic acid derivatives.
  • the other object of the invention is to provide novel compounds which are available as intermediates in the course of preparing the (-) pyridobenzoxazine carboxylic acid derivatives.
  • a low- priced compound (V) is employed as a starting material which is obtainable from 4-chloro-5-fluoro—2-halo-3- nitrobenzoic acid derivatives by the known process in the art (see: U.S.Pat. No. 5,237,060).
  • optically active (-) pyridobenzoxazine carboxylic acid derivatives of the invention are prepared by the following steps: i) reacting a compound (V) with a reactive material (VI) or (VII) in the presence of a base to obtain a compound (IV) ; ii) converting the compound (IV) to a compound (III) in an organic polar solvent and in the presence of a base; iii) reacting the compound (IIJ) with piperazine or N-mono- substituted-piperazine in an organic polar solvent in the presence of a base to obtain a novel compound (II) by so- called one-pot reaction; and, iv) hydrolyzing and cyclizing the compound (II) in an organic solvent in the presence of metal hydroxide to give the optically active compound (I ) .
  • X represents a halogen atom
  • Z represents a leaving group
  • Y represents an oxygen or a sulfur atom
  • R b represents alkyl group having 1 to 5 carbon atoms, phenyl group or substituted phenyl group
  • R represents the same as R a above or R b -NH-
  • X includes halogen atom such as chlorine atom and fluorine arom.
  • Z includes halogen atom such as chloride atom and fluorine atom; carboxylate group; and, alkoxy group.
  • R 2 includes lower alkyl group having 1 to 5 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group, n-butyl group, isobutyl group, t-pentyl group, n-pentyl group, isopentyl group and neopentyl group, preferably methyl group and ethyl group; phenyl group; substituted phenyl group such as p-methoxyl phenyl group, 3,5- dimethoxyphenyl group, 3, 5-dimethylphenyl group, 2,4,6- trimethylphenyl group, p-chlorophenyl group and p- fluorophenyl group; alkoxy group having 1 to 5 carbon atoms such as meth
  • R b includes lower alkyl group having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group, n-butyl group, isobutyl group, t-pentyl group, n-pentyl group, isopentyl group and neopentyl group; phenyl group; and, substituted phenyl group such as p-methoxyphenyl group, 3, 5-dimethoxyphenyl group, 3, 5-dimethylphenyl group, 2, , 6-trimethylphenyl group, p-chlorophenyl group and p- fluorophenyl group.
  • Ri includes hydrogen atom and lower alkyl group having having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group, n-butyl group, isobutyl group, t- pentyl group, n-pentyl group, isopentyl group and neopentyl group.
  • X and R represent the same above.
  • R a , R b , Z, and Y represent the same above.
  • the reactive material (VI) includes acylhalide, carboxylic acid anhydride, alkylchloroformate, cycloalkylchloroformate, alkylcarbonate, cycloalkylcarbonate, phenylchloroformate, substituted phenylchloroformate; and, the reactive material (VII) includes isocyanate and isothiocyanate .
  • the base includes metal carbonate, metal bicarbonate, metal alkoxide, 1, 8-diazabicyclo [5.4.0] -7- undecene(DBU) , 1, 4-diazabicyclo [2.2.2] octane (DABCO) , 1,5- diazabicyclo [4.3.0] -5-nonene (DBN) , pyridine, dimethylaminopyridine and trimethylamine, where potassium carbonate and sodium carbonate are preferably employed as the metal carbonate; potassium bicarbonate and sodium bicarbonate, as the metal bicarbonate; and, sodium methoxide and sodium ethoxide, as the metal alkoxide.
  • the compound (IV) obtained in Step 1 is converted to a compound (III ) in the presence of an organic polar solvent and 2.0 ⁇ 5.0 mole equivalents of base at a temperature of range of 18°C to 150 °C depending on the solvent and the base.
  • the organic polar solvent includes DMF(N,N'- dimethylformamide) , DMSG (dimethylsulfoxide) , dioxane, acetonitrile, tetrahydrofuran and acetone.
  • the base includes metal carbonate, metal bicarbonate, metal alkoxide, DBU (1, 8-diazabicyclo [5.
  • the compound (III) is reacted with 1.0 ⁇ 3.0 mole equivalents of piperazine or N-mono-substituted- piperazine to obtain a novel compound (II) , in the presence of an organic polar solvent and 2.0 ⁇ 5.0 mole equivalents of a base at a temperature range of 18°C to 120°C.
  • the compound (III) may be employed in a purified state or non- purified state and, the organic solvent includes DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran and acetone, and the base includes metal carbonate, metal bicarbonate, metal alkoxide, DBU, DABCO, DBN, pyridine, dimethylaminopyridine and trimethylamine, where the metal carbonate, the metal bicarbonate and the metal alkoxide are the same above.
  • the organic solvent includes DMF, DMSO, dioxane, acetonitrile, tetrahydrofuran and acetone
  • the base includes metal carbonate, metal bicarbonate, metal alkoxide, DBU, DABCO, DBN, pyridine, dimethylaminopyridine and trimethylamine, where the metal carbonate, the metal bicarbonate and the metal alkoxide are the same above.
  • the piperazine or N-mono-substituted-piperazine is represented by the following formula (VIII)
  • the substituted-piperazine includes N- methypiperazine, N-ethylpiperazine, N-n-propylpiperazine, N-isopropylpiperazine, N-t-butylpiperazine, N-sec- butylpiperazine, N-n-butylpiperazine, N- isobutylpiperazine, N-t-pentylpiperazine, N-n- pentylpiperazine, N-isopentylpiperazine and N- neopentylpiperazine .
  • the compound (II) is converted to a compound (I) by hydrolysis and cyclization of compound (II) via one or two steps .
  • the compound (I) is obtained by refluxing the compound (II) in the presence of 3.0 ⁇ 6.0 mole equivalents of metal hydroxide and an organic solvent with heating.
  • the metal hydroxide includes potassium hydroxide and sodium hydroxide
  • the organic solvent includes alcohol, tetrahydrofuran and a mixed solvent of one of the said solvent and water.
  • mixing ratio may be 100:0 to 25:75(v/v)
  • mixing ratio of tetrahydrofuran and water it may be 100:0 to 25:75(v/v).
  • the compound (II) was hydrolyzed to give an intermediate compound (II-l) , which is , in turn, converted to the compound (I) by hydrolysis and cyclization of compound (II- 1) in a purified or non-purified state.
  • the compound (II) was hydrolyzed to form an intermediate compound (II-2) , which is , in turn, converted to the compound (I) by cyclization of compound (I1-2 ) in a purified or non-purified state.
  • R and Ri represent the same above; and, M represents metal atom such as potassium and sodium.
  • the compound (II) is reacted with 1.0 ⁇ 2.0 mole equivalents of metal carbonate in a mixed solvent of alcohol and water to give an intermediate compound (II-l) , where the mixing ratio of alcohol and water in the mixed solvent may be 100:0 to 25:75(v/v), and the metal carbonate includes potassium carbonate and sodium carbonate .
  • the compound (II) is reacted with 2.0 ⁇ 4.0 mole equivalents of metal hydroxide in alcohol to give an intermediate compound (II-2) , where the metal hydroxide includes potassium hydroxide and sodium hydroxide.
  • the compound (I) is obtained by refluxing the intermediate compound (II-l) or (II-2) in the presence of 1.0 ⁇ 3.0 mole equivalents of metal hydroxide and an organic solvent, where the metal hydroxide includes potassium hydroxide and sodium hydroxide, and the organic solvent includes alcohol, tetrahydrofuran and a mixed solvent of one of the said solvent and water.
  • the mixed solvent of alcohol and water mixing ratio of alcohol and water may be 100:0 to 25:75(v/v), while in the case of the mixed solvent of tetrahydrofuran and water, it may be 100:0 to 25:75(v/v).
  • inorganic salt was removed by filtration and evaporated under a reduced pressure, and treated with 250ml of acetic acid ethyl ester and 250ml of water to fractionate an organic layer.
  • the organic layer was dried over anhydrous MgS0 4 , evaporated under a reduced pressure to give 52g(90%) of the titled compound.
  • the compound was further purified by dissolving in 150ml of ethylacetate/hexane (1/2, v/v) with heating and leaving to stand at room temperature, finally to give 32g(56%) of the pure titled compound.
  • optically active (-) pyridobenzoxazine carboxylic acid derivatives or pharmaceutically acceptable salt thereofs can be manufactured from the low-priced 4-chloro-5-fluoro-2- halo-3-nitrobenzoic acid in a simple and economical manner .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Quinoline Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention porte sur un procédé de préparation d'un dérivé optiquement actif de l'acide (-)pyridobenzoxazine carboxylique et de ses sels pharmacocompatibles à partir d'un précurseur d'(+)éthyl 2-(4-chloro-5-fluoro-2-halo-3-nitobenzoil)-3-[(1-hydroxypropy-2(S)-yl)amino]acrylate. Selon l'invention, le susdit dérivé peut être fabriqué simplement et économiquement à partir de dérivés économiques de l'acide 4-chloro-5-fluorobenzoïque.
PCT/KR2000/000145 1998-02-24 2000-02-23 Procede de preparation de derives de l'acide (-)pyridobenzoxazine carboxylique Ceased WO2000050428A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US09/674,323 US6316618B1 (en) 1998-02-24 2000-02-23 Process for preparing (-)pyridobenzoxazine carboxylic acid derivatives
DE60009807T DE60009807T2 (de) 1999-02-24 2000-02-23 Verfahren zur herstellung von (-)pyridobenzoxazin-carbonsäure-derivaten
EP00905443A EP1073662B1 (fr) 1999-02-24 2000-02-23 Procede de preparation de derives de l'acide (-)pyridobenzoxazine carboxylique
BRPI0005132-2A BR0005132B1 (pt) 1999-02-24 2000-02-23 processo para a preparação de derivados de ácido (-) piridobenzoxazina carboxìlico.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1999/0006093 1999-02-24
KR1019990006093A KR100309871B1 (ko) 1999-02-24 1999-02-24 (-)피리도벤즈옥사진 카르복실산 유도체의 제조방법

Publications (1)

Publication Number Publication Date
WO2000050428A1 true WO2000050428A1 (fr) 2000-08-31

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ID=19574927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2000/000145 Ceased WO2000050428A1 (fr) 1998-02-24 2000-02-23 Procede de preparation de derives de l'acide (-)pyridobenzoxazine carboxylique

Country Status (9)

Country Link
US (1) US6316618B1 (fr)
EP (1) EP1073662B1 (fr)
JP (1) JP3530784B2 (fr)
KR (1) KR100309871B1 (fr)
CN (1) CN1125073C (fr)
BR (1) BR0005132B1 (fr)
DE (1) DE60009807T2 (fr)
ES (1) ES2215024T3 (fr)
WO (1) WO2000050428A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6747156B2 (en) 2000-03-21 2004-06-08 Independent Pharmaceutica Ab Method of producing 6-substituted (s)-nicotine derivatives and intermediate compounds
US7220861B2 (en) 2002-12-21 2007-05-22 Yuhan Corporation Processes for preparing quinolonecarboxylate derivatives
US7425628B2 (en) 2001-10-03 2008-09-16 Teva Pharmaceutical Industries Ltd. Methods for the purification of levofloxacin
US7629458B2 (en) 2001-10-03 2009-12-08 Teva Pharmaceutical Industries Ltd. Preparation of levofloxacin and hemihydrate thereof

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100494882B1 (ko) * 1999-08-21 2005-06-14 경동제약 주식회사 (-)-9-플루오로-2,3-디히드로-3(ｓ)-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-7ｈ-피리도[1,2,3-데]-1,4-벤즈옥사진-6-카르복실산의 제조방법
AU2002365416A1 (en) * 2001-11-29 2003-06-10 Teva Pharmaceutical Industries Ltd. Methods for the purification of levofloxacin
KR100542600B1 (ko) * 2004-05-17 2006-01-11 주식회사 카이로켐 광학활성 (s)-피리도벤즈옥사진 카르복실산 반수화물 유도체의 제조 방법
KR100704641B1 (ko) * 2004-07-21 2007-04-06 주식회사유한양행 고순도의 레보플록사신 제조방법
CN1332962C (zh) * 2005-07-12 2007-08-22 武汉人福药业有限责任公司 一种合成甲磺酸帕珠沙星中间体的方法
CN102827075A (zh) * 2011-06-14 2012-12-19 四川科伦药物研究有限公司 一种西他沙星中间体的合成方法
CN113717100B (zh) * 2021-10-11 2023-03-17 郑州工业应用技术学院 一种培氟沙星醛缩4-芳基氨基硫脲类衍生物的制备方法

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US477273A (en) * 1892-06-21 Norman f
JPH01165589A (ja) * 1987-12-22 1989-06-29 Dai Ichi Seiyaku Co Ltd 魚類感染症の予防・治療剤
WO1990012799A1 (fr) * 1989-04-26 1990-11-01 The Upjohn Company Agents de pyrido(1,2,3-de)-1,4-benzoxazinone a action antibacterienne

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JPS5746986A (en) 1980-09-02 1982-03-17 Dai Ichi Seiyaku Co Ltd Pyrido(1,2,3-de)(1,4)benzoxazine derivative
DK170473B1 (da) 1985-06-20 1995-09-11 Daiichi Seiyaku Co S(-)-pyridobenzoxazinforbindelser
DE3522406A1 (de) 1985-06-22 1987-01-02 Bayer Ag Verfahren zur herstellung von 1,8-verbrueckten 4-chinolon-3-carbonsaeuren
US5237060A (en) 1985-12-10 1993-08-17 Bayer Aktiengesellschaft Process of preparing enantiomerically pure 1,8-bridged 4-quinolone-3-carboxylic acids
US4777253A (en) 1986-04-25 1988-10-11 Abbott Laboratories Process for preparation of racemate and optically active ofloxacin and related derivatives
KR0125115B1 (ko) 1994-03-22 1997-12-05 김은영 (-)피페라진 벤즈옥사진 유도체의 제조방법
KR0142139B1 (ko) * 1994-03-22 1998-07-01 김은영 (+)2-벤조일-3-[(프로피-2(s)-일)아미노]아크릴레이트 유도체의 제조방법
GB2301354A (en) 1995-04-04 1996-12-04 Resolution Chemicals Limited Preparation for intermediates for quinolone antibiotics

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US477273A (en) * 1892-06-21 Norman f
JPH01165589A (ja) * 1987-12-22 1989-06-29 Dai Ichi Seiyaku Co Ltd 魚類感染症の予防・治療剤
WO1990012799A1 (fr) * 1989-04-26 1990-11-01 The Upjohn Company Agents de pyrido(1,2,3-de)-1,4-benzoxazinone a action antibacterienne

Non-Patent Citations (1)

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Title
See also references of EP1073662A4 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6747156B2 (en) 2000-03-21 2004-06-08 Independent Pharmaceutica Ab Method of producing 6-substituted (s)-nicotine derivatives and intermediate compounds
US7425628B2 (en) 2001-10-03 2008-09-16 Teva Pharmaceutical Industries Ltd. Methods for the purification of levofloxacin
US7629458B2 (en) 2001-10-03 2009-12-08 Teva Pharmaceutical Industries Ltd. Preparation of levofloxacin and hemihydrate thereof
EP1451194B2 (fr) † 2001-10-03 2009-12-16 Teva Pharmaceutical Industries Ltd. Preparation de levofloxacine hemihydrate
US7220861B2 (en) 2002-12-21 2007-05-22 Yuhan Corporation Processes for preparing quinolonecarboxylate derivatives

Also Published As

Publication number Publication date
KR20000056615A (ko) 2000-09-15
DE60009807D1 (de) 2004-05-19
JP3530784B2 (ja) 2004-05-24
ES2215024T3 (es) 2004-10-01
KR100309871B1 (ko) 2001-10-29
EP1073662A4 (fr) 2002-04-17
BR0005132B1 (pt) 2010-06-15
JP2000247980A (ja) 2000-09-12
US6316618B1 (en) 2001-11-13
CN1125073C (zh) 2003-10-22
CN1294592A (zh) 2001-05-09
DE60009807T2 (de) 2005-04-28
EP1073662B1 (fr) 2004-04-14
BR0005132A (pt) 2001-01-02
EP1073662A1 (fr) 2001-02-07

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